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Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer.

ABSTRACT: Background:Bevacizumab is a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) and used for treatments of various cancers. Due to the high costs of bevacizumab treatments, a biosimilar provides an affordable alternative therapy for cancer patients. Methods:In this randomized, double-blind, multicenter, phase 3 study, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor were enrolled and randomized (1:1) into IBI305 or bevacizumab groups. Patients received 6 cycles of paclitaxel/carboplatin plus IBI305 or bevacizumab 15 mg/kg intravenously followed by IBI305 or bevacizumab 7.5 mg/kg maintenance until disease progression, unacceptable toxicity or death. The primary endpoint was confirmed objective response rate (ORR) by an independent radiological review committee (IRRC) and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. Results:A total of 450 NSCLC patients were enrolled (224 in IBI305 group and 226 in bevacizumab group). ORRs were 44.3% for IBI305 and 46.4% for bevacizumab, and the ORR ratio was 0.95 (90% CI: 0.803 to 1.135), within the predefined equivalence margin of 0.75 to 1.33. No significant difference in PFS (7.64 vs. 7.77 m, P=0.9987) was observed between the 2 groups. Serious adverse events (AEs) occurred in 33.5% (75/224) of patients in the IBI305 group and 37.6% (85/226) in the bevacizumab group. AEs ? grade 3 were similar in the IBI305 and bevacizumab groups [84.4% (189/224) vs. 89.8% (203/226), P=0.085]. Conclusions:IBI305 is similar to bevacizumab in terms of efficacy and safety. Trial registration:Clinicaltrials.org Identifier: NCT02954172. Registered on 3 November 2016. Https://clinicaltrials.gov/.

SUBMITTER: Yang Y

PROVIDER: S-EPMC6976344 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer.

Yang Yunpeng Y Wu Bin B Huang Linian L Shi Meiqi M Liu Yunpeng Y Zhao Yanqiu Y Wang Lijun L Lu Shun S Chen Gongyan G Li Baolan B Xie Conghua C Fang Jian J Yang Nong N Zhang Yiping Y Cui Jiuwei J Song Yong Y Zhang Cuiying C Mei Xiaodong X Cao Bangwei B Yang Lan L Cheng Ying Y Ying Kejing K Sun Tao T Ren Biyong B Yu Qitao Q Liao Zijun Z Pei Zhidong Z Wang Mengzhao M Zhou Jianying J Yu Shiying S Feng Guosheng G Wan Huiping H Wang Huaqing H Gao Shegan S Wang Jinliang J An Guangyu G Geng Yi Y Ji Yanxia Y Yuan Ying Y Ma Shenglin S Jia Zhongyao Z Hu Mu M Zhou Hui H Yu Jie J Sun Xing X Zhang Li L

Translational lung cancer research 20191201 6

<h4>Background</h4>Bevacizumab is a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) and used for treatments of various cancers. Due to the high costs of bevacizumab treatments, a biosimilar provides an affordable alternative therapy for cancer patients.<h4>Methods</h4>In this randomized, double-blind, multicenter, phase 3 study, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor rec ...[more]

PMID: 32010577

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Project description:BackgroundPF-06439535 is a bevacizumab biosimilar. We aimed to compare the efficacy and safety of PF-06439535 with that of reference bevacizumab (Avastin®) sourced from the EU (bevacizumab-EU), each with paclitaxel and carboplatin, in the first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC).MethodsIn this double-blind, parallel-group study, we recruited patients from 159 centers in 27 countries. Participants were randomized 1:1 to receive PF-06439535 plus paclitaxel and carboplatin or bevacizumab-EU plus paclitaxel and carboplatin on day 1 of each 21-day cycle for 4-6 cycles, followed by blinded monotherapy with PF-06439535 or bevacizumab-EU until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study. Randomization was stratified by region, sex, and smoking history. The primary endpoint was objective response rate (ORR) in accordance with RECIST 1.1, based on responses achieved by week 19 and confirmed by week 25.ResultsBetween 21 May 2015 and 14 November 2016, 719 patients were randomized to the PF-06439535 group (n = 358) or the bevacizumab-EU group (n = 361). As of data cutoff for analysis of the primary endpoint (8 May 2017), 45.3% (95% confidence interval [CI] 40.01-50.57) of patients in the PF-06439535 group and 44.6% (95% CI 39.40-49.89) of patients in the bevacizumab-EU group achieved an objective response by week 19 that was confirmed by week 25. The unstratified ORR risk ratio was 1.015 (95% CI 0.863-1.193; 90% CI 0.886-1.163), and the unstratified ORR risk difference was 0.653% (95% CI - 6.608 to 7.908); all three CIs fell within pre-specified equivalence margins. Using final data after study completion (22 December 2017), no notable differences in progression-free survival or overall survival were observed between the groups. The most frequently reported grade 3 or higher treatment-emergent adverse events were hypertension, neutropenia, and anemia. There were no clinically meaningful differences in safety, pharmacokinetics, or immunogenicity across treatment groups.ConclusionAmong patients with advanced non-squamous NSCLC, PF-06439535 demonstrated similarity to bevacizumab-EU in terms of efficacy. Safety profiles for the two treatments were comparable.Trial registrationClinicalTrials.gov, NCT02364999.FundingPfizer.

Project description:BackgroundPembrolizumab combined with chemotherapy is now first-line standard of care in advanced non-small cell lung cancer. This real-life study aimed to assess efficacy and safety of carboplatin-pemetrexed plus pembrolizumab in advanced non-squamous non-small cell lung cancer.MethodsCAP29 is a retrospective, observational, multicenter real-life study conducted in 6 French centers. We evaluated efficacy of first-line setting chemotherapy plus pembrolizumab (November 2019 to September 2020) in advanced (stage III-IV) non-squamous non-small cell lung cancer patients without targetable alterations. Primary endpoint was progression-free survival. Secondary endpoints were overall survival, objective response rate and safety.ResultsWith a median follow-up of 4.5 months (0 to 22 months), a total of 121 patients were included. Baseline characteristics were: median age of 59.8 years with 7.4% ≥75 years, 58.7% of males, 91.8% PS 0-1, 87.6% of stage IV with ≥3 metastatic sites in 62% of cases. Patients had brain and liver metastases in 24% and 15.7% of cases, respectively. PD-L1 was <1% (44.6%), 1-49% (28.1%) and ≥50% (21.5%). Median progression-free survival and overall survival achieved 9 and 20.6 months, respectively. Objective response rate was 63.7% with 7 prolonged complete responses. Survival benefit seemed to be correlated with PD-L1 expression. Brain and liver metastases were not statistically associated with decreased overall survival. Most common adverse events were asthenia (76%), anemia (61.2%), nausea (53.7%), decreased appetite (37.2%) and liver cytolysis (34.7%). Renal and hepatic disorders were the main causes of pemetrexed discontinuation. Grade 3-4 adverse events concerned 17.5% of patients. Two treatment-related deaths were reported.ConclusionsFirst-line pembrolizumab plus chemotherapy confirmed real-life efficacy for patients with advanced non-squamous non-small cell lung cancer. With median progression-free survival and overall survival of 9.0 and 20.6 months, respectively and no new safety signal, our real-life data are very close to results provided by clinical trials, confirming the benefit and the manageable toxicity profile of this combination.

Project description:ImportanceChemotherapy is a mainstay treatment of metastatic non-small cell lung cancer. However, little is known about the comparative risk of hospitalization associated with commonly used chemotherapy regimens.ObjectiveTo evaluate the real-world association of specific lung cancer chemotherapy regimens with measures of acute hospital care (primary objective) and survival (secondary objective).Design, setting, and participantsRetrospective, propensity-matched, cohort study using the Surveillance, Epidemiology, and End Results-Medicare linked data for cancer diagnoses between 2008 and 2013, with follow-up through 2014. Patients were Medicare beneficiaries 66 years of age or older receiving initial chemotherapy for treatment of stage IV, nonsquamous, non-small cell lung cancer. Analyses were performed between September 2017 and April 2018.ExposuresReceipt of chemotherapy with carboplatin-pemetrexed or carboplatin-paclitaxel, with or without concurrent bevacizumab.Main outcomes and measuresThe primary outcome was risk of hospitalization within 30 days of chemotherapy initiation. Secondary measures included cumulative 90-day hospitalizations, 90-day mean hospital-free survival time, and overall survival.ResultsOf the 3310 eligible patients, 1823 received carboplatin-pemetrexed, and 1487 received carboplatin-paclitaxel. The median age at diagnosis was 73 years (interquartile range, 69-77 years), 1784 patients (53.9%) were men, and 2909 patients (87.9%) were non-Hispanic white. In total, 2182 patients were included in the propensity-matched analysis. The 30-day hospitalization risk was 20.7% (95% CI, 18.3%-23.1%) among patients receiving carboplatin-pemetrexed vs 26.0% (95% CI, 23.4%-28.6%) among patients receiving carboplatin-paclitaxel (5.3% difference; P?=?.003). The 90-day cumulative hospitalizations did not differ significantly between the 2 treatment groups; however, the 90-day mean hospital-free survival time was improved for patients receiving carboplatin-pemetrexed (68.4 days [95% CI, 66.5-70.4 days] vs 63.6 days [95% CI, 61.6-65.7 days]; P?=?.001). The median survival time was 9.0 months (95% CI, 8.4-9.5 months) with carboplatin-pemetrexed therapy vs 7.6 months (95% CI, 7.0-8.4 months) with carboplatin-paclitaxel therapy (P?=?.005). Stratified analyses showed no association of bevacizumab use with hospitalization risk or survival when combined with either chemotherapy regimen.Conclusions and relevanceThe findings from this study suggest that patients receiving carboplatin-pemetrexed compared with those receiving carboplatin-paclitaxel have a lower 30-day hospitalization risk, a greater 90-day hospital-free survival, and improved overall survival. Information about hospitalization risk may provide valuable context for evaluating real-world cancer treatment outcomes.

Project description:PURPOSE To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. METHODS We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non-small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m(2)) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity. Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425C-->T was 1.84 (95% CI, 0.77 to 4.48; P = .19). CONCLUSION Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.

Project description:Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide. The initial treatment of lung cancer depends on the definition of the tumor type and its staging. The most common treatment is chemotherapy, and the first-line treatment is a combination of carboplatin and paclitaxel. Although this treatment has good efficacy, there is a high prevalence of adverse events, particularly hematological reactions. Studies on new biomarkers related to these adverse events, such as circulating microRNAs (miRNAs/miRs), are important for optimizing the quality of life of patients. miRNAs have high stability in several biological fluids and they have specific expressions in different tissues or pathologies. Thus, the present study aimed to assess the relationship between circulating miRNAs and adverse hematologic reactions caused by treatment with carboplatin + paclitaxel in patients with lung cancer. Blood was collected from patients before and 15 days after chemotherapy for hematological adverse reaction analysis, microarray and quantitative (q)PCR validation. Adverse reactions were classified according to the Common Terminology Criteria for Adverse Events v4.0. Microarray analysis was performed using plasma from six patients without anemia and six patients with anemia, and nine miRNAs were differentially expressed. miR-1273g-3p, miR-3613-5p and miR-455-3p, identified using microarray, were assessed using qPCR in 20 patients without anemia and 26 patients with anemia. Bioinformatic analyses of miR-455-3p were performed using miRWalk, the Database for Annotation, Visualization and Integrated Discovery and GeneMania software. Microarray analysis of patients with and without anemia revealed nine significant differentially-expressed plasma miRNAs among these patients. Of these, miR-1273g-3p, miR-3613-5p and miR-455-3p were chosen for further assessment. Only miR-455-3p demonstrated a significant reduction in expression (P=0.04) between the groups before chemotherapy with carboplatin + paclitaxel. Bioinformatics analysis of miR-455-3p revealed a relationship between this miRNA and the hematopoietic pathway, particularly with respect to the RUNX family transcription factor 1 (RUNX1) and TAL bHLH transcription factor 1, erythroid differentiation factor (TAL1) genes. The most prevalent adverse reactions in patients with lung cancer treated with carboplatin + paclitaxel were hematological, particularly anemia. This adverse reaction, caused by dysfunction of the hematopoietic system, may be explained by a possible association between the important genes in this system, RUNX1 and TAL1, and hsa-miR-455-3p.

Dataset Information

Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer.

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Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer.

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